Process for the preparation of [S(-) amlodipine - L (+)- hemitartarate]

ABSTRACT

The present invention relates to a process for the preparation of [S(−)amlodipine-L(+)-hemi taratarte] from RS amlodipine base using L(+) tartaric acid in the presence of dimethyl sulfoxide.

FIELD OF THE INVENTION

[0001] The present invention relates to a process for the preparation of[S(−)amlodipine-L(+)-hemi taratarte] from RS amlodipine base using L(+)tartaric acid in the presence of dimethyl sulfoxide.

BACKGROUND OF THE INVENTION

[0002] Amlodipine and its salts are long acting calcium channel blockersand are useful for the treatment of cardiovascular disorders. RacemicAmlodipine is currently being used as its besylate in the treatment ofhypertension and angina. The preparation of racemic compound isdescribed in European patent 0089167. Amlodipine is racemic compound andhas chiral center at 4 position of the dihydropyridine ring.

[0003] It has also been reported that the R(+) isomer is a potentinhibitor of smooth muscle cell migration (PCT/EP-94/02697). The S(−)isomer is having calcium channel blocker activity while the R(+) isomershas little or no calcium channel blocking activity.

[0004] Prior art for the preparation of R and S enantiomers ofamlodipine are a) resolution of amlodipine azide ester with opticallyactive 2-methoxy-2-phenylethanol (J. Med. Chem., 29, 1696, 1986. J. E.Arrowsmith, S. F. Campbell, P. E. Cross, J. K. Stabs, R. A., Burges andEP Appl. 0331315A) or b) resolution of Amlodipine base with opticallyactive camphanic acid [J. Med. Chem., 35, 3341, 1992, S. Goldman., J.Stoltefuss and L. Born) or c) resolution of RS.-amlodipine base to R(+)and S(−) isomer with L or D tartaric acid respectively in organicsolvent DMSO {Peter L., Spargo U.S. Pat. No. 6,046,338; (2000), PCT95/25722 (1995)] which indicate the use of both tartaric acids isessential.

THE DISADVANTAGES

[0005] The main disadvantages of the prior art are:

[0006] 1. The use of unnatural tartaric acid for the separation ofS(−)amlodipine

[0007] 2. The use of costlier camphanic acid or2-methoxy-2-phenylethanol as a resolving agents.

OBJECTS OF THE INVENTION

[0008] The main object of the invention is to develop a technology forthe preparation of S(−)amlodipine from racemic amlodipine usingnaturally occurring L-tataric acid.

SUMMARY OF THE INVENTION

[0009] Accordingly, the invention provides a new and efficient processfor the preparation of [S(−)amlodipine-L(+)hemi tartarte] in good yieldwith high enantiomeric purity by reacting RS amlodipine base with L(+)tartaric acid in an organic solvent at a temperature ranging from 20-35°C. for a period ranging from 16 to 24 hours, separating by filtrationsolid [R(+)amlodipine-L(+)-hemi taratarte], seeding the filtrate toobtain solid [S(−) amlodipin-L(+)-hemi taratarte], filtering andrecrystallising the solid, basifying to obtain S(−) amlodipine.

[0010] In one embodiment of the present invention the organic solventused for the reaction is dimethyl sulfoxide.

[0011] In another embodiment of the present invention 0.5 mole of L(+)tartaric acid is used for the reaction.

[0012] In another embodiment the solvent used for crystallization isselected from the group consisting of methanol, ethanol and butanol.

[0013] In another embodiment of the invention basification is done usingmetal hydroxides, carbonates or aq. Ammonia.

DETAILED DESCRIPTION OF THE INVENTION

[0014] The unique feature of the invention is preferentialcrystallization of enantiomer salt with respect to quantity of DMSO andtime. The process of resolution of RS amlodipine using L(+) tartaricacid is shown in the scheme below:

[0015] The process of the present invention is described herein belowwith reference to examples which are illustrative only and should not beconstrued to limit the scope of the present invention in any manner.

EXAMPLE-1

[0016] Amlodipine hemi L tartarate-mono-DMSO Solvate mp 160-162° C.[α]^(t)=+24.32 (c=1, R(+) Amlodipine-hemi-L-tartarate mono DMSO Solvateand S(−) Amlodipine-hemi-L tartarate mono DMSO Solvate from (RS)Amlodipine.

[0017] To a stirred solution of 10.50 gm (0.0256 mole), of RS Amlodipinein 30 ml of DMSO was added a solution of 1.93 (0.128) mole (0.5 equiv)of L(+) Tartaric acid in 30 ml DMSO. The solid starts separating fromclear solution within 5-10 min. This was stirred for 3 hrs. and thesolid was filtered off, washed with acetone and dried to give 6.66 gm,46.15% R(+) MeOH). The filtrate was seeded with S(−)amlodipine hemi L(+)tartarate salt. and left overnight the solid was filtered off and washedwith 10 ml acetone and dried to give 6.41 gm, 44.4% S(−) amlodipine-hemiL(+)-tartarate mono DMSO solvate.mp 169.5-171.5° C.=−14.1 (c=1, MeOH)90% de by chiral HPLC. (J.Chrom., B 693, 367 (1997) J. Luksa, Dj. Josic,B. Podobinc, B. Furlan, M. Kremser]

EXAMPLE-2

[0018] RS Amlodipine L(+)tartarate mono DMSO Solvate from RS Amlodipine

[0019] The procedure as described in example 1 was repeated and thereaction was kept overnight. The solid filtered and dried to yeidl 14gm, 97.9% RS Amlodipien L(+) tartarate mono DMSO solvate. Mp 148.5-151°C. (c=1 MeOH) 3.3% de by chiral HPLC.

EXAMPLE-3

[0020] S(−)Amlodipine hemi L(+)tartarate monohydrate from S(−)Amlodipine-hemi-L-(+)tartarate monohydrate DMSO Solvate—Methanol asSolvent.

[0021] 50 gms of S(−) Amlodipine-hemi-L(+)-tartarate mohohydrate DMSOsolvate was dissolved in 250 ml refluxing methanol (30 min). Thesolution was kept overnight at room temperature (25-28° C.) withstirring. The solid was collected by filtration, washed with 100 mlmethanol and dried at 50° C. in vacuo (2 hrs till constant wt.) to give35 gm (80%). S(−)Amlodipine-hemi-L(+)-tartarate monohydrate. Mp 171-172°C.=114.1 (c=1, MeOH); 90% de chiral HPLC.

EXAMPLE-4

[0022] S(−)Amlodipine hemi L(+)-tartarte mohohydrate from S(−)Amlodipine-hemi-L-(+)tartarate monohydrate DMSO Solvate—Ethanol asSolvent.

[0023] The procedure was followed as mentioned in example 3 was usingethanol (150 ml) instead of methanol. The solid obtained was collectedby filtration, washed with 50 ml cold ethanol and dried at 50° C. invacuo (2 hrs till constant wt.) to give 30 gms (68%). S(−)Amlodipinehemi L(+)tartarate monohydrate mp 172.5-174° C.=17.44 (C=1, MeOH), 97%de chiral HPLC.

EXAMPLE-5

[0024] S(−)Amlodipine from (S) (−)Amlodipine hemi L(+)tartartemohonydrate.

[0025] S(−)Amlodipine hemi L(+)tartarate mohohydrate (30 gms) wasslurried in 60 ml CH₂Cl₂ and 60 ml (6%) aqueous ammonia for 30 min. Theorganic solution was separated and washed with water. The organicextract was dried to give solid. The solid was filtered and dried atroom temperature under vacuo to give 20 gms (82%) S(−)amlodipine mp108-109° C. 30.55 (c=1, MeOH), 97.4% ee by chiral HPLC.

EXAMPLE-6

[0026] S(−)Amlodipine from S(−)Amlodipine hemi L(+)tartarte mono DMSOSolvate

[0027] S(−)Amlodipine hemi L(+)-tartarate mono DMSO solvate (30 gms) wasslurried in 60 ml CH₂Cl₂ and 60 ml (6%) aqueous ammonia for 30 min. Theorganic solution was separated and washed with water. The organicextract was dried over anhydrous sodium sulphate and concentrated. Theresidue was triturated with hexane to give solid 20.1 gms (92%)S(−)amlodipine. Mp107-107.5° C. 27.3 (c=1, MeOH), 90% ee by chiral HPLC.

We claim:
 1. A process for the preparation of [S(−)amlodipine-L(+)-hemitartarte which comprises reacting RS amlodipine base with L(+)tartaricacid in an organic solvent at a temperature ranging from 20-35° C. forthe period ranging from 16 to 24 hours, separating the solid[R(=)amlodipin-L(+)-hemi tartarate] by filtration, seeding the filtrateto obtain solid [S(−)amlodipin-L(+)-hemi tartarate] by precipitation,filtering the solid and basifying to obtain [S(−)amlodipine-L(+)-hemitartarte.
 2. A process claimed in claim 1 wherein the solvent is DMSO 3.A process claimed in claim 1 wherein the solvent to amlodipine ratio is5-6 ml/gm of amlodipine.
 4. A process claimed in claim 1 whereinL-tartaric acid employed is about 0.5 mole per mole of amlodipine.
 5. Aprocess claimed in claim 1 wherein the solvate precipitated isS(−)smlodipine hemi L(+)-tartarate mono DMSO solvate.
 6. A processclaimed in claim 1 wherein a stirred solution of RS Amlodipine in DMSOwas added to a solution of L(+)Tartaric acid in DMSO, the solid obtainedseparated by filtration, washed with acetone, dried to give R(+) MeOH),the filtrate seeded with S(−)amlodipine hemi L(+)tartarate salt, thesolid so obtained filtered off and washed with acetone and dried to giveS(−)amlodipine-hemi L(+)-tartarate mono DMSO solvate.